Aminobenzenesulfonamidohalopyrazines and method of preparing same



Patented July 12, 1949 l slmfrss "PATENT OFFICE AMINOBENPZENESULFONAMIDOHALOPY- RAZINE S- AND METHOD OF PREPARING SAME Elmore H. NortheygBound Brook, and'John-S. Webb, Wenonah, *N. J., assignors to American Gyanamid Company, NewliYork, N. Y'., a corporation of Maine hNo'iDrawing. Application June 26,19 5,

Serial No. 6013714 "NH? SOJNL -01 HG] The rcactionis unusualin that one ofthe reactantsyhas two -#-N'H2 groups whereas the other has "-a plurality of' halogens. Despite thisfact, arm-nobenzenesulfonamidohalopyrazines are obtained with goodyiel-ds in a relatively high state of purity. Thereisno evidence 'of the formation of a clisulfanilamidopyraz-ine, asmight be ex" pected.

"The reaction is also unusual in that excellent yieldsof product areobtainedwithoutthe'use of "copper powder, zcoppersalts or other catalytic agents which add e-xpense 'andpurification difficultiee to the; process.

As illustrated, the reaction involves the formation of a halogenacidl Itismdesirable, therefore, that an acid-'binding'agent'be present in the react on mixtureztorcombine with the. acid: as it is liberated during the reaction. Suitable substances forlthisnpurpose include sodium carbonate, potassium carbonate, barium carbonate, sodium tbicarbonate, sodium r and potassium hysdI'OXi'dE, trisodium phosphate, and the like. In cgeneralmanysubstance which "will react with a hal ogerracidtto form a saltstabl'ewat thetemperature of the reactionlmayebe usedlas an acid-binding agent.

The reaction iscarried out at-elevated temperatures, preferably within-the range of about 125 C. to 160 C. Temperatures outside these limits, for example from about 120 C. to 175 C., may be employed, at least during part of the reaction period.

In g-eneral, the reaction may be carried out by merely mixing together the desired polyhalopyrazine, aminobenzenesulfonamide, and the 9 Claims. (Cl.260-v23916) acid-bindingagent. The substantiallydry ,mixtureis then heated within the tem-perature range indicated above. Completionof the reaction may be conveniently determined by" observation of therate at which-acid'is formed in theflreaction mixture, for example by noting the evolution or carbon dioxidegas :when a carbonate 5 is used "as the :acid biIrdi-ng substance. The reaction mixture iscollected, dissolved in watenand, then treated to recover unreacted polyhalopyrazine and sultanilamide. The:2-sulfonamidobenzenehalopyrazine reaction products may be. recovered from its aqueous'solution in the form of the relatively insoluble freeoacid by treating a solution at one of itssaltelwith an acid strongerithan the free :acidic "2 -:sulfonamidobenzenehalopyrazine.

Oi course, the reaction may be carriedputin cthe presence'oi an inertwsolventa if desired. The solvent 1 should: a have :a boiling point above about 130 C. otherwise tzthe use of pressure vessels; is

necessary i to attain the 1 reaction temperatures required.

*The hydrogen attached to the nitrogenpatom of the-amide group is acidic 1 in character and it is zpossibla-thereiore, to. prepare alkali: metal, alkaline earth metal, and other cationic salts: of the product. These .:may be prepared :by simply treating the 1 free sulfonami'de with wan aqueous solution-rot a=suitable :alkaline substance. The alkali :metal andralkaline earth metal salts; are more water; soluble 'thanthe free 'sulfonamide and are useful in this. form fortamany' purposes.

The :new: llaminobenzenesulfonamidohalopyrazines: of the rprezsenty invention. possess unusual itherapeuticpropertieswin thatrthey are relativehf non-toxic: and are highly :effective r in the :treat- .ment of zbacterial infectionssvchile atlthe same "time a they are extremely effective in; :the treatment of certain diseases caused by protozoa; for

:' example, :coccidiosis, "causedzby Eimcria tenella, in poultry, sheep cattle, rabbitaand other animals These new compounds and, in particular,

2 sulfanilamido mchloropyrazine, are a many times more efiectiverin the treatment of coccidlosi's in chickens than the :most 'efiective sulfonamide yet xdescribed.

Our invention :nowabe illustrated by means of the following examples in which the preparation of dichloropyrazines, which are in themselves new compounds, and the preparation of certain aminobenzenesulfonamidohalopyrazines is described. It will be understood that the particular details thereof are subject to variation within the scope of the invention as described hereinabove Example 1 The dichloropyrazines employed in this and the succeeding examples were prepared by the vapor phase chlorination of pyrazine. A solution of pyrazine in water is vaporized and mixed with chlorine at approximately 350 C. The mixed vapors are passed through a glass or stainless steel tube and heated between 400 C. and 500 C. for two to three seconds. The vapors are condensed and collected in a receiving vessel in which the products separate into two layers. The oily layer consists essentially of chloropyrazines. The isomeric 2,3-, 2,5-, and 2,6-dichloropyrazines may be recovered from the oil by separating the fraction boiling between 94 and 107 C. at 50 mm. pressure. When this fraction is allowed to crystallize at room temperature the 2,6-dichloropyrazine contained therein separates and may be recovered by filtration. The product is purified by recrystallizing from anhydrous alcohol. The 2,6-dichloropyrazine has a melting range of 53.153.8 C. and a dipole moment of 1.52M.

By crystallizing the dichlorcpyrazine mother liquors at successively lower temperatures crystals of 2,3-dichloropyrazine and 2,5-dichloropyrazine are obtained. These crystals may be purified by melting, partial refreezing, and filtration. The 2,3-dichloropyrazine has a melting range of from 22 to 24 C. and a dipole moment of 2.07 1. whereas the 2,5-dichloropyrazine has a melting range of -4 to 1 C. and a dipole moment of 1.14

To prepare 2-sulfanilamido-3=chloropyrazine a suitable reaction vessel is charged with 100 parts by weight of 2,3-dichloropyrazine, 115 parts by weight of sulfanilamide and 92 parts by weight of potassium carbonate (dehydrated and pulverized). The nearly dry charge is then heated with mixing. At an internal temperature of 123, the,

charge becomes more fiuid and evolution of carbon dioxide begins. The temperature of the charge rapidly rises to 152 where water and di= chloropyrazine reflux in the condenser. During the next minutes, the charge gradually thickens. When evolution of gas stops, the charge is cooled below 100, and is dissolved by the addition of 630 parts by weight of water, except for a small amount of unchanged dichloropyrazine. The solution is then distilled with steam to recover about parts of unchanged 2,3-dichloropyrazine. The solution remaining in the still is then cooled to 10 where the unchanged sulfanilamide crystallizes from solution. When crystallization is complete, the sulfanilamide is filtered, washed with water, and dried, giving a recovery of about 17 parts by weight of sulfanilamide suitable for re-use.

The mother liquor and washings are combined and the 2-sulfanilamido-3-chloropyrazine precipitated by adjusting the pH to 3 with hydrochloric acid. The product is separated by filtration, washed free of salt and dried. The yield of crude 2-sulfanilamido-3-chloropyrazine is 115 (88%) of theoretical) parts by weight. It may be purified by dissolving as the sodium salt, treat- 4 ing with an activated charcoal and re-precipitat ing with a mineral acid, or by other purification procedures obvious to those skilled in the art. The product as obtained on drying at 45 C'. is a monohydrate having a melting point of 156.8 to 157.0 C.

Example 2 By following the procedure of Example 1, starting with the isomeric 2,5-dichloropyrazine, 2-sulianilamido-5-chloropyrazine was prepared. This was obtained as an anhydrous product, melting at 211.9-213.7 C.

Example 3 By following the procedure of Example 1, startwith 2,6-dichloropyrazine, 2-sulfanilamido-6- chloropyrazine was obtained, having a melting range of 234.8-235.4 C.

Example 4 Metaaminobenzenesulfonamide was used to replace the sulfanilamide of Example 1. The product, 2-metanilamido-5-ch1oropyrazine, had a melting point of 176.9 C.

We claim:

1. Para-aminobenzenesulfonamidohalo p y r a zines and salts thereof.

2. Para aminobenzenesulfonamidochloropyrazines.

3. 2-sulfanilamido3-chloropyrazine.

4. 2-sulfanilamido-5-chloropyrazine.

5. 2-sulfanilamido-6-ch1oropyrazine.

6. A method of preparing aminobenzenesul- 1 fonamidohalopyrazines which comprises mixing together and heating sulfanilamide with a polyhalopyrazine and an acid-binding substance at temperatures within the range to C.

7. A method of preparing aminobenzenesulfonamidohalopyrazines which comprises mixing together and heating sulfanilamide with a dichloropyrazine and an alkali metal carbonate at temperatures within the range 120 to 175 C.

8. A method of preparing aminobenzenesulfonamidochloropyrazines which comprises mixing together and heating sulfanilamide with a dichloropyrazine and potassium carbonate at temperatures within the range 120 to 175 C.

9. A method of preparing 2-sulfanilamido-5- chloropyrazine which comprises mixing together and heating in the presence of an alkali metal carbonate 2,5-dichloropyrazine and sulfanilamide.

ELMORE H. NORTHEY. JOHN S. WEBB.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,259,222 Ewins et a1. Oct. 14, 1941 2,403,776 Winnek July 9, 1946 2,423,108 Moore et al. July 1, 1947 OTHER REFERENCES Southern Med. J., vol. 34, April, 1941, pp. 446, 447. Copy in 260-2396. 

